Fibroblast growth factors (FGFs) comprise a family of 22 members that govern a wide spectrum of cell biological behaviors such as proliferation, cell death, migration and gene expression. Increased expression of specific members of this family, such as <I>Fgf8</I>, play an important role in the progression of both breast and prostate cancer. To understand how such abnormal <I>Fgf8</I> expression affects cell function in cancer, our long-term goal is to determine the normal role of <I>Fgf8</I>, during vertebrate embryogenesis, using the mouse as a model system. <I>Fgf8</I> is expressed in a variety of regions of the embryo that may be termed "organizers": regions that are a source of signals that pattern and thus "organize" the surrounding tissue. Previously we have generated an allelic series generated at the <I>Fgf8</I> locus (Meyers et al. 1998 <I>Nature Genetics</I> 18:136), as well as Cre-mediated tissue-specific knockouts (Lewandoski et al. 2000 <I>Nature Genetics</I>, 26:460; Lewandoski 2001 <I>Nature Reviews Genet.</I> 2:743; Lewandoski 2007 <I>Handb Exp Pharmaco</I> 178: 235) and revealed a role for <I>Fgf8</I> in organizers that control gastrulation, limb, and brain development. Recently we have produced a valuable mouse line (T-Cre) that expresses Cre specifically throughout all embryonic mesodermal lineages, thus allowing us to control gene expression in these lineages. This line is useful to bypass the embryonic lethal phenotypes of genes that affect early development, yet allows the study of the role of such genes throughout much of the embryo (Verheyden et al, 2005 <I>Development</I>, 132: 4235.) Inactivation of <I>Fgf8</I> with TCre has revealed that <I>Fgf8</I> plays a central role in cell survival and gene expression during kidney development (Perantoni et al 2005, <I>Development</I>, 132: 3859). Another surprising insight emerging from these studies is that <I>Fgf8</I> is not required for several mesodermal signaling centers that control the process of somite formation, where it was thought to play a role. To investigate this, we are studying mutants in which <I>Fgf8</I> and each of the other five <I>Fgfs</I> expressed in these regions are simultaneously inactivated. Importantly, we have uncovered a redundant role between <I>Fgf4</I> and <I>Fgf8</I> in somite formation. This functional redundancy has implications for cancer as both FGFs have been found to be aberrantly active in testicular tumors. Furthermore this redundancy as implications for evolution as the same FGFs play compensatory roles in limb development. One of the intriguing insights that has emerged from these studies is that at different stages of embryogenesis FGF signaling plays different roles in cell migration, proliferation, patterning, and survival. How is this diversity of response achieved? To answer this question, we are studying downstream targets of FGF signaling. One set of such target genes is the homeobox genes <I>Gbx1</I> and <I>2</I>. The role of the mouse <I>Gbx2</I> gene during neurulation and particularly in defining the mid/hindbrain organizer has been well documented. We have extended this analysis by studying a hypomorphic (partial-loss-of-function) <I>Gbx2</I> allele, which has revealed that <I>Gbx2</I> is required at certain threshold levels for different parts of the brain (Waters and Lewandoski 2006 <I>Development</I>, 133: 1991). Compared to <I>Gbx2</I> relatively little has been reported about <I>Gbx1</I>. We recently described the cloning and embryonic expression pattern of <I>Gbx1</I> and defined regions of potential molecular redundancy with <I>Gbx2</I>. (Waters et al 2003 <I>Gene Exp. Patterns.</I> 3:313). We are currently studying mice with an allelic series at the <I>Gbx1</I> locus to study its function during development, including its role in FGF signaling and its interactions with <I>Gbx2</I> .